Field of the Invention
The present invention relates to various muscarinic cholinergic receptor-binding compounds, gamma-emitting radioisotope derivatives thereof, intermediate and methods for the production thereof and the use of the said radioisotope derivatives as radiopharmaceuticals in the assay and external imaging of myocardial tissue and other organs containing muscarinic cholinergic receptors.
It is known that muscarinic cholinergic receptors are concentrated in myocardial and other tissue. It is theorized that these receptors are involved in the action of drugs or biochemicals in the myocardial tissue and that changes in the concentration of the receptor in the myocardial tissue are a function of a disease state therein or in other tissue containing the receptors.
It has been established that various compounds function both in vitro and in vivo as muscarinic cholinergic receptor binders or antagonists. These compounds have a high affinity for and competitively bind with the receptor. It has been established that various 3-quinuclidinyl glycolates are effective muscarinic cholingergic receptor binders. It has further been suggested that tritium-labeled 3-quinuclidinyl glycolates may be utilized as radiotracers for various assay procedures involving myocardial tissue. See Eckelman et al, J. Nucl. Med., 20, 350 (1979) and Gibson et al, J. Nucl. Med. 20, 865 (1979).
There are numerous disadvantages inherent in the use of tritium-labeled radiotracers. For example, numerous problems are associated with "counting" beta-emissions of tritium-labled compounds. Liquid scintillator must be added to each sample which is a time-consuming and expensive procedure. Toluene is the typical scintillator liquid employed which is presently subject to strict, environmental sanctions because it is not miscible with water thereby rendering its disposal problematical. In addition, beta-counting procedures are plagued with problems of chemluminescence and quenching which are absent in gamma-counting.
Tl-201 is presently employed for the detection and quantification of myocardial infarcts. However, the radiohalogens such as I-123 and Br-77 have better imaging characteristics in that their higher gamma energies can be detected with increased sensitivity and positional resolution as compared with the lower gamma energy of Tl-201 (80 Ke V X-rays).
Since the size of the infarct is related to mortality and residual function, improved resolution will mean improved prognosis and evaluation of drug therapy. The radiohalogens F-18 and Br-75 are positron emitters which offer the unique capabilities of resolution and quantification associated with such decay characteristics.
The unique radio imaging properties of Technetium-99m (Tc-99m) render radio imaging and radio assay agents containing the Tc-99m radioisotope more commercially viable than those agents containing other radioisotopes. Tc-99m has become the radioisotope of choice because:
(1) It has a six hour half-life thereby rendering it most efficient as an external imaging agent.
(2) Unlike other radioisotopes used as radio-tracers, there is no beta-component in the gamma-emission of Tc-99m.
(3) Technetium-99m is relatively inexpensive and widely available from molybdenum generators.
(4) There is a low absorbed radiation dose connected with the use of Tc-99m.
It is an object of the present invention to provide various 3-quinuclidinyl glycolates and gamma-emitting radioisotope containing 3-quinuclidinyl glycolates useful for muscarinic cholinergic receptor assays, and imaging of the myocardium and in vitro muscarinic cholinergic assay and tissue imaging techniques.